A. Inflammatory Bowel Disease
Inflammatory Bowel Disease ("IBD") is the collective term used to describe two chronic, idiopathic inflammatory diseases of the gastrointestinal tract: ulcerative colitis ("UC") and Crohn's disease ("CD"). UC and CD are considered together because of their overlapping clinical, etiologic, and pathogenetic features. From a therapeutic and prognostic standpoint, however, it is important to distinguish them.
IBD occurs world-wide and is reported to afflict as many as two million people. Onset has been documented at all ages; however, IBD predominately begins in young adulthood. The three most common presenting symptoms of IBD are diarrhea, abdominal pain, and fever. The diarrhea may range from mild to severe and is often accompanied by urgency and frequency. In UC, the diarrhea is usually bloody and may contain mucus and purulent matter as well. Anemia and weight loss are additional common signs of IBD. Reports of an increasing occurrence of psychological problems, including anxiety and depression, are perhaps not surprising secondary effects of what is often a debilitating disease that occurs in people in the prime of life.
B. Methods of Diagnosing IBD
A battery of laboratory, radiological, and endoscopic evaluations are combined to derive a diagnosis of IBD and to assess the extent and severity of the disease. Nevertheless, differentiating UC from CD, as well as other types of inflammatory conditions of the intestines, such as irritable bowel syndrome, infectious diarrhea, rectal bleeding, radiation colitis, and the like, is difficult, because the mucosa of the small and large intestines reacts in a similar way to a large number of different insults. Once other types of bowel disorders have been ruled out, the final diagnosis is often made on the basis of the progression of the disease. In many patients, though, the colitis must still be regarded as indeterminate because of the overlapping features of UC and CD, particularly with CD of the colon.
1. Early Symptoms of IBD
The leading early symptoms of UC and CD are chronic recurrent diarrhea, bloody diarrhea, recurrent abdominal pain, nausea, weight loss general evidence of inflammation without any obvious explanation (fever, raised ESR, leucocytosis, thrombocytosis and dysproteinenemia or anemia). Among these symptoms, diarrhea and anemia are more characteristic of UC while pain and weight loss and marked evidence of inflammation are more common in CD. While the history and physical examination of a patient can help, the final confirmation of the diagnosis has traditionally been made endoscopically, histologically and, in relation to the small intestine, radiologically as well.
2. Endoscopic and/or Radiologic Examination
An endoscopic examination of the bowel can reveal important changes in mucosal appearances which can aid the physician in diagnosing IBD.
Unlike CD, UC is a disease of the mucosa and is confined to the large intestine. UC usually begins in the rectum, although it may involve the entire colon at the time of presentation. When UC spreads, it spreads proximally and continuously, without skipping areas. Hence, it is important to take multiple biopsy specimens from different sites of involved and apparent uninvolved mucosa. In some patients, UC remains localized to the rectum or to the left side of the colon.
The mucosa in acutely active UC appears to be hyperemic, granular and friable, while CD shows lymphoid follicles, aphthoid lesions and flat ulcers. Despite its name, inflammation rather than ulceration is the cardinal feature of UC. Ulcerations may or may not be present in UC. Occasionally, inflammation and ulceration vary in severity in different parts of the colon, including the rectum, giving the false impression of skip areas and rectal sparing, the latter of which are features of CD and are of diagnostic importance for that disorder.
The mucosa of CD exhibits patchy involvement with edema, hyperemia, and ulcerations. The ulceration is a prominent feature of CD. Both superficial and deep undermining or cleft-like ulcers occur. They may be linear or serpiginous. Occasionally, the combination of edema with ulcerations creates a cobblestone appearance that is seen radiologically and endoscopically. Inflammatory polyps, as in UC, may occur.
3. Histological Examination
The cardinal histological features in UC include vascular congestion, edema, goblet cell mucin depletion, crypt abscess formation, and inflammatory cell infiltration of the lamina propria. Crypt abscesses are collections of neutrophils that invade the crypt epithelium and accumulate within the lumen of the crypts. Ulcerations, if they occur, are superficial and only become penetrating to the propria muscularis when the disease is fulminant and acute toxic dilatation of the colon occurs.
Histology in CD shows the characteristic findings of granuloma formation with epithelioid and giant cells. However, these features are found in only 20-40% of biopsies. Transmural inflammation is also typical of CD, and even more typical is its disproportionate distribution (submucosa&gt;mucosa). The mucosa shows infiltration by granulocytes with preservation of normal numbers of goblet cells. Lymphocytes and plasma cells are found in the lamina propria, and lymphoid aggregates are present. Lastly, aphthoid lesions are a typical histological feature in the early stages.
4. Determination of ANCA Status
The presence of anti-neutrophil cytoplasmic antibodies ("ANCAs") can easily be detected in a blood sample, for example, by immunofluorescence assay or a fixed neutrophil ELISA as detailed in Saxon, et al., J. Allergy Clin. Immunol. Vol. 86 No. 2, pp. 202-210 (1990) and incorporated herein by reference. The prevalence of positive ANCA in patients with UC ranges from 50 to 86%. This UC-associated ANCA has perinuclear immunofluorescence binding pattern which is different from other ANCAs. Moreover, the presence of ANCA is highly specific for UC compared with other forms of colitis. Although a proportion of CD exhibit ANCA, it is at a much lower titre than UC.
Thus the ANCA status of a patient (positive indicating UC and negative indicating CD) is another factor that aids the physician in the diagnosis of IBD. ANCAs also have an increased frequency among the clinically healthy relatives of UC patients compared with environmental and ethnically matched controls. Therefore, ANCA status, in combination with family history of IBD, has also aided physicians in predicting a subjects susceptibility to IBD.
To date, a diagnosis of UC or CD is quite subjective and depends upon host of procedures aimed at confirming the suspected diagnosis. The initial symptoms are often confused for non-chronic bowel disorders by physicians unfamiliar with IBD. Consequently, IBD is often goes mistreated and undiagnosed until the disease shows its chronicity which results in referral of the patient to a specialist. The imprecise and subjective nature of endoscopic and radiologic examination can result in a misdiagnosis between UC and CD or indeterminate diagnosis even when the IBD is suspected.
Histological examination and ANCA status do provide greater certainty of an accurate diagnosis, but the problems of differentiating between the two diseases based on the histological findings are often underestimated. There is no single histological criterion which is proof of one or the other disease. The epithelial cell granuloma for example, which is often accorded a key role in the diagnosis of CD is only to be found in about 20% of bioptic specimens from such patients. They can also occur in other diseases. Unfortunately, the patient must often suffer as the disease progresses before a definitive diagnosis can be made.
The selective identification of UC as opposed to CD or other inflammatory conditions of the intestines carries important prognostic and therapeutic implications. For example, when colectomy is indicated, the type of IBD involved determines which surgical options are appropriate. Surgery (total colectomy) does represent a cure in UC, though a dramatic one. In CD, surgery is never curative. Continent procedures such as the ileorectal pull-through (mucosal proctectomy) or the Kock pouch may be desirable in UC, but are contraindicated in CD.
C. Inflammation and Intercellular Adhesion Molecules
Although the cause(s) of UC and CD is not known, there is general agreement that genetics is important in a person's susceptibility to UC and CD and that the immune system is responsible for mediating the tissue damage in these diseases. A wide range of immunologic abnormalities have been reported in these disorders, but none has yet been sufficiently reliable to be of diagnostic value.
What characterizes the various forms of IBD is a failure to down regulate the normal self-limited inflammatory response of the gut. Inflammation is the response of vascularized tissue to infection or injury. Clinically it is accompanied by four classic signs: redness, heat, pain and swelling. Its course may be acute or chronic.
At the cellular level, inflammation involves the adhesion of leukocytes (white blood cells) to the endothelial wall of blood vessels and their infiltration into the surrounding tissues. In normal inflammation, the infiltrating leukocytes phagocytize invading organisms or dead cells, and play a role in tissue repair and the immune response. However, in pathologic inflammation, infiltrating leukocytes can cause serious and sometimes deadly damage.
Recognizing that leukocyte infiltration is the cause of much inflammation-related pathology and that leukocyte adhesion is the first step in infiltration, investigators have recently focused attention on the mechanism of leukocyte binding to the endothelium cell surface. Studies show that binding is mediated by cell-surface molecules on both endothelial cell and leukocytes, which act as receptor and ligand. For a review of the roles of leukocyte integrins, immunoglobulin (Ig) gene family members, and selections in the leukocyte rolling, attachment, and transendothelial migration, the reader is directed to Springer, T. A., et al., Nature, 346: 425-433 (1990); Springer, T. A., et al., "Leukocyte Adhesion Molecules Structure Function and Regulation," New York: Springer-Velag (1990); Lasky, L. A., Science 258: 964-969 (1992); McEver, R. P., Curr. Opin. Cell. Biol. 4: 840-849 (1992); Lipsky, P. E., "Structure, Function and Regulation of Molecules Involved n Leukocyte Adhesion," New York: Springer-Verlag (1993); Hogg, N. and Landis, R. C., Curr. Opin. Immunol. 5: 383-390 (1993), all of which are incorporated herein by reference.
Transendothelial migration begins with leukocyte rolling which is largely brought about by the selections Lasky, et al., 1992. The later stages of endothelial migration involve activation of leukocyte integrins and binding of leukocytes to the endothelial cells which express Ig-like proteins including intercellular adhesion molecule-1 ("ICAM-1"). The interaction of leukocyte integrins with the Ig-like proteins leads to firm attachment and actual migration across the endothelial surface (see, Smith, C. W., et al., J. Clin. Invest. 82: 1746-1756 (1988) and Smith, C. W., "Transenothelial Migration." ed. Harlan, J. M. and Liu, D. Y. New York: W. H. Freeman & Co. pp. 83-115 (1992), incorporated herein by reference). Thus, a genetic variation in these inflammatory cell adhesion molecules would be an important variable in the susceptibility, diagnosis and treatment of multifactorial disease processes like IBD which involve inflammatory or immunological responses.
The availability of a diagnostic marker that would readily distinguish UC from CD of the colon, independent of or in combination with existing diagnostic methods, would represent a major clinical advance which would aid in therapeutic management of IBD and the design of more specific treatment modalities. Accordingly, there has existed a need for a convenient and reliable method to distinguish UC from CD for diagnostic, prognostic and therapeutic purposes.